This proposal is for studies on normal myelinated and pathological (demyelinated and remyelinated, dysmyelinated) axons. Recent evidence indicated that, in normal myelinated fibers, the nodal membrane exhibits different properties from the internodal axon membrane. This differentiation is especially important in the context of the demyelinating and dysmyelinating diseases, and in some peripheral neuropathies, because in these disorders current may be shunned through non-myelinated (previously internodal) axolemma. Conduction properties may also be changed following remyelination, since nodal spacing is altered, so that nodels of Ranvie are formed at previous internodal sites. Our studies indicate that is is possible to cytochemically mark normal nodel membrane. Observations on the initial segment, which exhibits properties similar to those of nodal membrane, and which can be stained selectively and in its entirety, demonstrate that it is possible to determine the apatial extent of large regions of specialized membrane. We now plan to use our cytochemical techniques, and morphometric methods, to study normal and pathological myelinated axons, with particular emphasis on the question of structural-functional alterations in the axolemma of de- and remyelinated fibers. In particular, we plan to study the following inter-related problems: What is the temporal relation of differentiation of the nodal axolemma to myelinogenes; does the specialization of the nodal membrane precede, coincide with, or follow myelinating. What are the properties of the axolemma in de- and remyelinated fibers; does the axolemma exhibit any structural alterations following chronic demyelination; how is the formation of new nodes during remyelination related to the differentiation of the original nodes? What are the properties of the dysmyelinated axolemma, and what is the response of the dysmyelinated axon to subsequent demyelination? What are the morphological correlates, in terms of axon membrane structure and myelin morphometrics, of metabolic neuropathies? In what ways is the extracellular nodal gap substance altered in various axonal pathologies.